Plasma kallikrein (EC.3.4.21.34) is a serine protease that is normally synthesized in the liver and circulates in the plasma by binding to high molecular weight kininogen (HMWK) or as prekallikrein, an inactive precursor (zymogen) of kallikrein. It is activated by proteolytic cleavage by Factor XIIa and contains an endopeptidase activity for cleaving peptide bonds after Arg or Lys residues.
Plasma kallikrein plays an important role in a variety of physiologic progesses, including, but not limited to, blood pressure regulation, the contact activation pathway of blood coagulation, fibrinolysis, inflammation, and pain.
The main physiologic regulator of kallikrein is C1 esterase inhibitor, or C1 INH. C1 INH is a potent inhibitor of Factor XIIa, and under normal conditions the inhibition of Factor XIIa prevents the conversion of prekallikrein to kallikrein and the subsequent generation of bradykinin from HMWK by activated kallikrein. Of note, patients with mutations that reduce CI INH activity have inappropriately high plasma kallikrein activity that leads to elevated levels of bradykinin, a potent vasodilator and pain mediator. Thus, inherited C1 INH deficiency is the cause of hereditary angioedema (HAE), a debilitating and life-threatening condition characterized by severe swelling, edema, and pain.
Bradykinin is normally degraded by angiotensin converting enzyme (ACE), and patients treated with ACE inhibitors for blood pressure reduction may display elevated bradykinin levels and suffer from a syndrome termed acquired angioedema.
While HAE can be effectively controlled by administration of purified or recombinant CI INH, it has been demonstrated that both plasma kallikrein inhibitors and bradykinin receptor antagonists are also effective in the treatment of HAE.
Elevated bradykinin levels are also associated with pain, inflammation, neutrophil recruitment, hypotension and septic shock. Furthermore, the inhibition of the kallikrein-bradykinin system may be useful in a variety of clinical situations, including, but not limited to, edemas (including diabetic macular edema, cerebral edema, and radiation-induced edema), diabetic retinopathy, retinal vein occlusion, intracerebral hemorrhage, stroke, systemic lupus, allergic rhinitis, controlling vascular leakage and blood loss during surgery, disseminated intravascular coagulation, inflammatory bowel disease, inflammation resulting from cardiopulmonary bypass, ischemia-reperfusion injury, and inflammatory or rheumatoid arthritis.
Given the many functional roles played by kallikrein, there remains a need for kallikrein inhibitors having pharmacokinetic and pharmacodynamic properties suitable for therapeutic application. The properties include, but are not limited to, high potency, high specificity for plasma kallikrein as compared to related protease, chemical and physical stability, ease of formulation, metabolic stability, appropriate pharmacokinetics, low toxicity, and good absorption from the intestinal tract (i.e. oral bioavailability).